Bottom Line:
Signal transducer and activator of transcription (STAT) proteins are latent transcription factors that mediate a wide range of actions induced by cytokines, interferons, and growth factors.The rate of lymphoma induction was markedly enhanced by immunization or by the introduction of TCR transgenes.These data demonstrate the oncogenic potential of dysregulated expression of a STAT protein that is not constitutively activated, and that TCR stimulation can contribute to this process.

ABSTRACTSignal transducer and activator of transcription (STAT) proteins are latent transcription factors that mediate a wide range of actions induced by cytokines, interferons, and growth factors. We now report the development of thymic T cell lymphoblastic lymphomas in transgenic mice in which Stat5a or Stat5b is overexpressed within the lymphoid compartment. The rate of lymphoma induction was markedly enhanced by immunization or by the introduction of TCR transgenes. Remarkably, the Stat5 transgene potently induced development of CD8+ T cells, even in mice expressing a class II-restricted TCR transgene, with resulting CD8+ T cell lymphomas. These data demonstrate the oncogenic potential of dysregulated expression of a STAT protein that is not constitutively activated, and that TCR stimulation can contribute to this process.

fig1: Anti-HA Western blotting of splenic and thymic lysates from two Stat5b transgenic lines (TG1 and TG2) and one Stat5a line (TGA). WT lysates are included as controls.

Mentions:
Stat5a and Stat5b are highly-related proteins that are required for normal lactation, growth, hematopoiesis, and immune function (20–26). We generated Stat5a and Stat5b transgenic mice, using a vector containing the H-2Kb promoter and IgM enhancer, in order to evaluate distinctive versus overlapping actions of these highly homologous proteins (>90% identical; reference 27) within the lymphoid system. Two Stat5b founder lines (TG1, TG2) and one Stat5a line that expressed the appropriate transgene in the immune system were evaluated (Fig. 1; reference 15). Both Stat5a and Stat5b transgenic mice have increased splenic CD8+ T cells at the earliest point examined (12 d; reference 15). Unexpectedly, as the mice aged, many developed striking lymphadenopathy that we noted at a median age of 205 d (range 78–456 d, Table I and Fig. 2, A and B), with enlarged thymuses (unpublished data), and spleens (Fig. 2 C). Normal lymph node architecture was disrupted by neoplastic lymphocytes (Fig. 2 D) with cytologic features consistent with the diagnosis of T cell lymphoblastic lymphoma (Fig. 2 E). The first 20 lymphomas occurred in 15 Stat5b transgenic mice (14 from the TG1 and one from the TG2 transgenic lines), and five Stat5a transgenics (Table I). The Stat5b transgenic line with the highest expression within the thymus (TG1) had the highest rate of tumor formation (25% of 60 mice over 4 mo old), the Stat5a transgenic line had intermediate rate of tumor formation (8% of 65 mice over 4 mo old), while Stat5b TG2 line had only 1 lymphoma out of 20 mice over 4 mo old, correlating thymic Stat5 transgenic expression (Fig. 1, lanes 3, 5, and 9) and lymphoma formation. Initially, mice were bred onto Stat5a−/−, Stat5b−/−, or Stat5a−/−/Stat5b−/− backgrounds as part of a study to compare the actions of Stat5a and Stat5b, but lymphomas have also developed on a WT background (Table I).

fig1: Anti-HA Western blotting of splenic and thymic lysates from two Stat5b transgenic lines (TG1 and TG2) and one Stat5a line (TGA). WT lysates are included as controls.

Mentions:
Stat5a and Stat5b are highly-related proteins that are required for normal lactation, growth, hematopoiesis, and immune function (20–26). We generated Stat5a and Stat5b transgenic mice, using a vector containing the H-2Kb promoter and IgM enhancer, in order to evaluate distinctive versus overlapping actions of these highly homologous proteins (>90% identical; reference 27) within the lymphoid system. Two Stat5b founder lines (TG1, TG2) and one Stat5a line that expressed the appropriate transgene in the immune system were evaluated (Fig. 1; reference 15). Both Stat5a and Stat5b transgenic mice have increased splenic CD8+ T cells at the earliest point examined (12 d; reference 15). Unexpectedly, as the mice aged, many developed striking lymphadenopathy that we noted at a median age of 205 d (range 78–456 d, Table I and Fig. 2, A and B), with enlarged thymuses (unpublished data), and spleens (Fig. 2 C). Normal lymph node architecture was disrupted by neoplastic lymphocytes (Fig. 2 D) with cytologic features consistent with the diagnosis of T cell lymphoblastic lymphoma (Fig. 2 E). The first 20 lymphomas occurred in 15 Stat5b transgenic mice (14 from the TG1 and one from the TG2 transgenic lines), and five Stat5a transgenics (Table I). The Stat5b transgenic line with the highest expression within the thymus (TG1) had the highest rate of tumor formation (25% of 60 mice over 4 mo old), the Stat5a transgenic line had intermediate rate of tumor formation (8% of 65 mice over 4 mo old), while Stat5b TG2 line had only 1 lymphoma out of 20 mice over 4 mo old, correlating thymic Stat5 transgenic expression (Fig. 1, lanes 3, 5, and 9) and lymphoma formation. Initially, mice were bred onto Stat5a−/−, Stat5b−/−, or Stat5a−/−/Stat5b−/− backgrounds as part of a study to compare the actions of Stat5a and Stat5b, but lymphomas have also developed on a WT background (Table I).

Bottom Line:
Signal transducer and activator of transcription (STAT) proteins are latent transcription factors that mediate a wide range of actions induced by cytokines, interferons, and growth factors.The rate of lymphoma induction was markedly enhanced by immunization or by the introduction of TCR transgenes.These data demonstrate the oncogenic potential of dysregulated expression of a STAT protein that is not constitutively activated, and that TCR stimulation can contribute to this process.

ABSTRACTSignal transducer and activator of transcription (STAT) proteins are latent transcription factors that mediate a wide range of actions induced by cytokines, interferons, and growth factors. We now report the development of thymic T cell lymphoblastic lymphomas in transgenic mice in which Stat5a or Stat5b is overexpressed within the lymphoid compartment. The rate of lymphoma induction was markedly enhanced by immunization or by the introduction of TCR transgenes. Remarkably, the Stat5 transgene potently induced development of CD8+ T cells, even in mice expressing a class II-restricted TCR transgene, with resulting CD8+ T cell lymphomas. These data demonstrate the oncogenic potential of dysregulated expression of a STAT protein that is not constitutively activated, and that TCR stimulation can contribute to this process.